Comprehensive analysis suggests simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD.

BACKGROUND: Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. NEW METHOD: In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. RESULTS: For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception. COMPARISON WITH EXISTING METHOD(S): We show how these processes accord with and provide insight on the waveforms reported in the literature. CONCLUSIONS: Finally we suggest that application of our method on averaged EEG/ERP data sampled from other paradigms may point at a similarly parsimonious set of underlying neurophysiologic processes which underlie the signal.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers.

OBJECTIVE: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. METHODS: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. RESULTS: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). CONCLUSIONS: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

Introducing a novel approach of network oriented analysis of ERPs, demonstrated on adult attention deficit hyperactivity disorder.

OBJECTIVE: Introducing a network-oriented analysis method (brain network activation [BNA]) of event related potential (ERP) activities and evaluating its value in the identification and severity-grading of adult ADHD patients. METHODS: Spatio-temporal interrelations and synchronicity of multi-sited ERP activity peaks were extracted in a group of 13 ADHD patients and 13 control subjects for the No-go stimulus in a Go/No-go task. Participants were scored by cross-validation against the most discriminative ensuing group patterns and scores were correlated to neuropsychological evaluation scores. RESULTS: A distinct frontal-central-parietal pattern in the delta frequency range, dominant at the P3 latency, was unraveled in controls, while central activity in the theta and alpha frequency ranges predominated in the ADHD pattern, involving early ERP components (P1-N1-P2-N2). Cross-validation based on this analysis yielded 92% specificity and 84% sensitivity and individual scores correlated well with behavioral assessments. CONCLUSIONS: These results suggest that the ADHD group was more characterized by the process of exerting attention in the early monitoring stages of the No-go signal while the controls were more characterized by the process of inhibiting the response to that signal. SIGNIFICANCE: The BNA method may provide both diagnostic and drug development tools for use in diverse neurological disorders.

Characterization of recovery and neuropsychological consequences of orbitofrontal lesion: A case study.

We present a case study of a patient with acquired prefrontal lesion involving mainly ventromedial and orbital structures (VM-PFD). The patient showed behavioral and emotional disturbances one year after the injury. In a follow-up examination seven years later, we evaluated her performance in tasks found theoretically to be sensitive to orbital and medial lesions. In contrast to our hypothesis, her performance was in the normal range. We suggest that a possible explanation for her magnificent recovery may include a high cognitive reserve and the specific characteristics of her injury.

High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

The origins of originality: the neural bases of creative thinking and originality.

Although creativity has been related to prefrontal activity, recent neurological case studies postulate that patients who have left frontal and temporal degeneration involving deterioration of language abilities may actually develop de novo artistic abilities. In this study, we propose a neural and cognitive model according to which a balance between the two hemispheres affects a major aspect of creative cognition, namely, originality. In order to examine the neural basis of originality, that is, the ability to produce statistically infrequent ideas, patients with localized lesions in the medial prefrontal cortex (mPFC), inferior frontal gyrus (IFG), and posterior parietal and temporal cortex (PC), were assessed by two tasks involving divergent thinking and originality. Results indicate that lesions in the mPFC involved the most profound impairment in originality. Furthermore, precise anatomical mapping of lesions indicated that while the extent of lesion in the right mPFC was associated with impaired originality, lesions in the left PC were associated with somewhat elevated levels of originality. A positive correlation between creativity scores and left PC lesions indicated that the larger the lesion is in this area the greater the originality. On the other hand, a negative correlation was observed between originality scores and lesions in the right mPFC. It is concluded that the right mPFC is part of a right fronto-parietal network which is responsible for producing original ideas. It is possible that more linear cognitive processing such as language, mediated by left hemisphere structures interferes with creative cognition. Therefore, lesions in the left hemisphere may be associated with elevated levels of originality.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

The neural correlates of understanding the other's distress: a positron emission tomography investigation of accurate empathy.

The purpose of the present study was to assess the relationship between brain metabolism and empathic response. Six right-handed healthy volunteers were scanned with PET and fluorodeoxyglucose twice: during an interview about neutral story themes and during an empathic response eliciting interview about a story of a character in distress. Metabolic values in the medial and superior frontal gyrus, occipitotemporal cortices, thalamus and the cerebellum were higher during empathic response than during the neutral theme interview. Furthermore, the subjects' empathy scores were positively correlated with metabolism in the medial aspects of the superior frontal gyrus. Our results suggest that empathy consists of both affective and cognitive components and hence may involve cortices that mediate simulation of emotional processing and mental state attribution.

The neuroanatomical basis of understanding sarcasm and its relationship to social cognition.

The authors explored the neurobiology of sarcasm and the cognitive processes underlying it by examining the performance of participants with focal lesions on tasks that required understanding of sarcasm and social cognition. Participants with prefrontal damage (n=25) showed impaired performance on the sarcasm task, whereas participants with posterior damage (n=16) and healthy controls (n=17) performed the same task without difficulty. Within the prefrontal group, right ventromedial lesions were associated with the most profound deficit in comprehending sarcasm. In addition, although the prefrontal damage was associated with deficits in theory of mind and right hemisphere damage was associated with deficits in identifying emotions, these 2 abilities were related to the ability to understand sarcasm. This suggests that the right frontal lobe mediates understanding of sarcasm by integrating affective processing with perspective taking.

Impaired "affective theory of mind" is associated with right ventromedial prefrontal damage.

OBJECTIVE: To examine the hypothesis that patients with ventromedial (VM) frontal lesions are impaired in the affective rather than cognitive facets of theory of mind (ToM). BACKGROUND: Prefrontal brain damage may result in impaired social behavior, especially when the damage involves the orbitofrontal/VM prefrontal cortex (PFC). It has been previously suggested that deficits in ToM may account for such aberrant behavior. However, inconsistent results have been reported, and different regions within the frontal cortex have been associated with ToM impairment. METHOD: The performance of 26 patients with localized lesions in the PFC was compared with responses of 13 patients with posterior lesions and 13 normal control subjects. Three ToM tasks differing in the level of emotional processing involved were used: second-order false belief task, understanding ironic utterances, and identifying social faux pas. RESULTS AND CONCLUSIONS: The results indicated that patients with VM (but not dorsolateral) prefrontal lesions were significantly impaired in irony and faux pas but not in second-order false belief as compared with patients with posterior lesions and normal control subjects. Lesions in the right VM area were associated with the most severe ToM deficit. These results are discussed in terms of the cognitive and affective facets of "mind-reading" processes mediated by the VM cortex.

Impairment in cognitive and affective empathy in patients with brain lesions: anatomical and cognitive correlates.

The present study was designed to examine the degree of impairment in cognitive and affective empathy among patients with focal brain lesions, and the contribution of specific cognitive abilities (such as cognitive flexibility and processing of emotional information), to empathy. The cognitive and affective empathic response of patients with localized prefrontal lesions (n=36) was compared to responses of patients with parietal lesions (n=15) and healthy control subjects (n=19). Results indicate that patients with prefrontal lesions (especially those with lesions involving the orbitoprefrontal and medial regions) were significantly impaired in both cognitive and affective empathy as compared to parietal patients and healthy controls. When the damage was restricted to the prefrontal cortex, either left- or right-hemisphere lesions resulted in impaired empathy. However, when the lesion involved the right hemisphere, patients with parietal lesions were also impaired. The pattern of relationships between cognitive performance and empathy suggested dissociation between the cognitive correlates of affective and cognitive empathy.

Novelty seeking and harm avoidance in Parkinson's disease: effects of asymmetric dopamine deficiency.

OBJECTIVES: Although changes in novelty seeking and harm avoidance have been reported among patients with Parkinson's disease (PD), the findings regarding the neurochemical correlates of such changes are inconsistent. This study was designed to examine the hypothesis that different patterns of motor and neurochemical asymmetry in PD may have contributed to the conflicting results. METHODS: Forty PD patients (divided into two groups according to initial asymmetry in dopamine deficit: left hemisphere, n = 22; right hemisphere, n = 18) and 17 age matched healthy controls completed the Tridimensional Personality Questionnaire (Cloninger, 1987). RESULTS: Only patients with greater dopamine loss in the left hemisphere showed reduced novelty seeking, whereas only patients with reduced dopamine in the right hemisphere reported higher harm avoidance than matched healthy controls. Novelty seeking was not associated with disease duration, current motor symptoms, or medication, whereas harm avoidance was significantly correlated only with the severity of bradykinesia and depression. CONCLUSIONS: Approach and avoidance reflect different patterns of dopaminergic asymmetry. Whereas reduced novelty seeking reflects deficit in the mesolimbic branch of ascending dopamine transmission in the left hemisphere, increased harm avoidance is associated with greater dopamine loss in the right striatum.

Cognitive performance following endarterectomy in asymptomatic severe carotid stenosis.

Cognition and the effects of carotid endarterectomy (CEA) were evaluated in 22 non-demented subjects with vascular risk factors (VRF) and asymptomatic severe carotid artery stenosis (ASCAS), 14 volunteers with VRF but without stenosis, and 24 healthy controls (HC) without VRF. Non-demented subjects with VRF, with or without carotid stenosis scored inferior to HC. It is concluded that carotid stenosis is not a primary cause of cognitive deterioration and CEA does not improve cognition in patients with ASCAS.

Characterization of empathy deficits following prefrontal brain damage: the role of the right ventromedial prefrontal cortex.

Impaired empathic response has been described in patients following brain injury, suggesting that empathy may be a fundamental aspect of the social behavior disturbed by brain damage. However, the neuroanatomical basis of impaired empathy has not been studied in detail. The empathic response of patients with localized lesions in the prefrontal cortex (n = 25) was compared to responses of patients with posterior (n = 17) and healthy control subjects (n = 19). To examine the cognitive processes that underlie the empathic ability, the relationships between empathy scores and the performance on tasks that assess processes of cognitive flexibility, affect recognition, and theory of mind (TOM) were also examined. Patients with prefrontal lesions, particularly when their damage included the ventromedial prefrontal cortex, were significantly impaired in empathy as compared to patients with posterior lesions and healthy controls. However, among patients with posterior lesions, those with damage to the right hemisphere were impaired, whereas those with left posterior lesions displayed empathy levels similar to healthy controls. Seven of nine patients with the most profound empathy deficit had a right ventromedial lesion. A differential pattern regarding the relationships between empathy and cognitive performance was also found: Whereas among patients with dorsolateral prefrontal damage empathy was related to cognitive flexibility but not to TOM and affect recognition, empathy scores in patients with ventromedial lesions were related to TOM but not to cognitive flexibility. Our findings suggest that prefrontal structures play an important part in a network mediating the empathic response and specifically that the right ventromedial cortex has a unique role in integrating cognition and affect to produce the empathic response.

Empathy deficits in Asperger syndrome: a cognitive profile.

Although lack of empathy has been considered a central characteristic of Asperger syndrome, quantitative and qualitative assessments of empathy in this syndrome are lacking. We present two cases of adolescents with Asperger syndrome who show extreme deficits on measures of both cognitive and affective empathy. Analysis of their performance on tasks assessing cognitive and affective processing did not reveal significant impairment in executive functions, nor in their ability to recognize emotions or the ability to create a mental representation of another person's knowledge. However, both patients were unable to integrate the emotional content with mental representations and deduce the other person's emotional state. These results suggest that impaired empathy in individuals with Asperger syndrome may be due to impaired integration of the cognitive and affective facets of the other person's mental state.

Preliminary analyses of Hebrew verbal fluency measures.

Hebrew language versions of phonemic and semantic fluency were administered to samples of normal control participants and individuals who had been hospitalized for 24 hr following a head injury. For the control sample, verbal fluency tasks were normally distributed and significantly correlated with education. The head injury sample's word generation was significantly lesser than that of the control's and not at all related to educational attainment. The findings provide evidence for the use of Hebrew fluency measures for clinical assessment and the need for collection of normative data across education levels.

Creating interpretation guidelines for the Hebrew trail making test.

The Hebrew language version of the Trail Making Test (TMT; Army Individual Test Battery, 1944) was administered to a group of normal control participants as well as a sample of outpatients approximately 1 year following a head injury. A ratio of TMT-B to TMT-A performance was computed in an effort to establish usable cutting scores for the Hebrew TMT. A ratio of 2.26 was observed to result in 63% sensitivity and 77% specificity for the sample, with positive predictive power of 71% and negative predictive power of 70%. A more stringent cutoff of 3.09 reduced sensitivity (22%) and negative predictive power (44%). In contrast, specificity (97%) and positive predictive power (86%) were greatly improved once the speed of TMT-A performance was also considered. The more conservative cutoff is considered appropriate when a finding is indicative of pathological performance.